title: miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia.
abstract: MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. In the present study, through a large-scale, genomewide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL-rearranged AML compared with both normal control and non-MLL-rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL-rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti-miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion-induced immortalization/transformation of normal mouse bone marrow progenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion-mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL-rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL-rearranged AML and can serve as a potential therapeutic target to treat this dismal disease.
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Colles
authors.initials: C
authors.lastname: Price
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Donglin
authors.initials: D
authors.lastname: Cao
authors.forename: Anissa
authors.initials: A
authors.lastname: Wiley
authors.forename: Chunjiang
authors.initials: C
authors.lastname: He
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.forename: Rejani B
authors.initials: RB
authors.lastname: Kunjamma
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.forename: Mengyi
authors.initials: M
authors.lastname: Xu
authors.forename: Gia-Ming
authors.initials: GM
authors.lastname: Hong
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Paul P
authors.initials: PP
authors.lastname: Liu
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D011519:Proto-Oncogenes / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein